title: Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia.
abstract: An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). We now report the first description of a homozygous patient and compare it to a series of heterozygous cases. The patient developed early-onset frontotemporal dementia without additional features. Neuropathological analysis showed c9FTD/ALS characteristics, with abundant p62-positive inclusions in the frontal and temporal cortices, hippocampus and cerebellum, as well as less abundant TDP-43-positive inclusions. Overall, the clinical and pathological features were severe, but did not fall outside the usual disease spectrum. Quantification of C9orf72 transcript levels in post-mortem brain demonstrated expression of all known C9orf72 transcript variants, but at a reduced level. The pathogenic mechanisms by which the hexanucleotide repeat expansion causes disease are unclear and both gain- and loss-of-function mechanisms may play a role. Our data support a gain-of-function mechanism as pure homozygous loss of function would be expected to lead to a more severe, or completely different clinical phenotype to the one described here, which falls within the usual range. Our findings have implications for genetic counselling, highlighting the need to use genetic tests that distinguish C9orf72 homozygosity.
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. p.fratta@prion.ucl.ac.uk
authors.forename: Pietro
authors.initials: P
authors.lastname: Fratta
authors.forename: Mark
authors.initials: M
authors.lastname: Poulter
authors.forename: Tammaryn
authors.initials: T
authors.lastname: Lashley
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Rohrer
authors.forename: James M
authors.initials: JM
authors.lastname: Polke
authors.forename: Jon
authors.initials: J
authors.lastname: Beck
authors.forename: Natalie
authors.initials: N
authors.lastname: Ryan
authors.forename: Davina
authors.initials: D
authors.lastname: Hensman
authors.forename: Sarah
authors.initials: S
authors.lastname: Mizielinska
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Waite
authors.forename: Mang-Ching
authors.initials: MC
authors.lastname: Lai
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.forename: Jason D
authors.initials: JD
authors.lastname: Warren
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Isaacs
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
mesh_terms: D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000473:pathology*; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009483:Neuropsychological Tests; D010375:Pedigree; D011506:Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins